1-(2-(2-substituted-3-indolyl)ethyl)-4-substituted-piperazines

ABSTRACT

NOVEL 1-(2-(2-SUBSTITUTED-3-INDOYL)ETHYL)-4-SUBSTITUTUED-PIPERAZINES HAVING PSYCHOMOTOR DEPRESSANT ACTIVITY.

United States Patent 3,562,2781-[2-(2SUBSTITUTED-3-INDOLYL)ETHYL]-4-SUB- STITUTED-PIPERAZINES SydneyArcher, Bethlehem, N.Y., assignor to Sterling Drug Inc., New York, N.Y.,a corporation of Delaware No Drawing. Continuation-impart of applicationSer. No. 733,250, May 31, 1968, which is a continuation-in-part ofapplication Ser. No. 634,899, May 1, 1967. This application Sept. 16,1969, Ser. No. 858,499 Claims priority, applicat i7on Canada, Apr. 16,1968,

1 .589 Int. Cl. C07d 51/70 U.S. Cl. 260268 17 Claims ABSTRACT OF THEDISCLOSURE Novel l-[2-(2-substituted 3indolyl)ethyl]-4-substituted-piperazines having psychomotor depressantactivity.

This application is a contin-uation-in-part of my prior co-pendingapplication S.N. 733,250, filed May 31, 1968, which is turn is acontinuation-in-part of my prior application S.N. 634,899, filed May 1,1967, both now abandoned.

The present invention relates to 1-[2-(2-substituted-3indolyl)ethyl]-4-substituted-piperazines having the formula where R islower-alkyl, hydroxy-lower-alkyl, phenyl, phenyl-unbranched-lower-alkyl,cinnamyl, pyridyl, or 2- pyrimidyl; R is carbo-lower-alkoxy, carboxy,sulfo (SO I-I), hydroxymethyl, lower-alkanoyloxymethyl, carbamyl,N-lower-alkylcarbamyl, N,N-di-lower-alkylcarbamyl, formyl, orisonitrosomethylene (CH=NOH), and alkali metal salts of compounds whereR is carboxy or sulfo; R is hydrogen, halogen, straight or unhinderedlower-alkyl, lower-alkoxy, lower-alkylmercapto, trifluoromethyl, orhydroxy; and R is hydrogen, halogen, straight or unhindered lower-alkylor lower-alkoxy, or R and R together represent methylenedioxy orethylenedioxy attached to adjacent carbon atoms, and wherein the benzenering of R as phenyl, phenyl-lower-alkyl, or phenyl-loweralkenyl isunsubstituted or substituted by methylenedioxy or ethylenedioxy or byone or two of the same or different members of the group consisting ofhalogen, lower alkyl, lower-alkoxy, lower-alkylmercapto,lower-alkylsulfinyl, lower-alkylsulfonyl, trifluoromethyl, or hydroxy.

As used herein, the terms lower-alkyl, lower-alkoxy, and lower-alkanoylmean such groups which can be either straight or branched, and whichcontain from one to seven carbon atoms, and thus the lower-alkyl moietyof such lower-alkyl or loWer-alkoxy groups represents, for example,methyl, ethyl, n-propyl, isopropyl, isobutyl, n-hexyl, and the like, andlower-alkanoyl represents, for example, formyl, acetyl, propionyl,u-methylhexanoyl, and the like.

As used herein, the term lower-alkenyl means loweralkenyl which can beeither straight or branched, and which can contain from three to sevencarbon atoms, and thus represents 1,3-(1-propenyl), 1,3-(1-butenyl),1,4-(2- butenyl) and the like.

In the above general Formula I, when R as phenyl, phenyl-lower-alkyl, orphenyl-lower-alkenyl is substituted in the benzene ring by one or two ofthe substituents ice enumerated above, the substituents can be the sameor different and can occupy any available carbon atom of the phenylring.

The compounds of Formula I where R is carbo-loweralkoxy are prepared byreacting a 2-carbo-lower-alkoxy- 3-(2-haloethyl)indole of Formula IIwith an appropriate l-substituted-piperazine of Formula III according tothe reaction:

where R R and R have the meanings given above, Alk representslower-alkyl, and X represents halogen. The re action can be carried outeither in the absence of a solvent or in an organic solvent inert underthe conditions of the reaction, for example methanol, ethanol,isopropanol, and the like, and in the presence of an acid-acceptor, thepurpose of which is to take up the hydrogen halide split out during thecourse of the reaction. Suitable acid-acceptors are alkali metalhydroxides, carbonates, or bicarbonates. An excess of thel-substituted-piperazine can also be used as the acid-acceptor.

The compounds of Formula II, required as intermediates in the abovereaction, are prepared by reaction of an appropriate phenylhydrazinewith a-keto-fi-valerolactone, under Fischer indole synthesis conditions,and conversion of the resulting 2-carboxy-3-(2-hydroxyethyl indole ofFormula IV to the compounds of Formula II as described hereinbelow. Thereactions are represented by the equations:

The a-keto-a-valerolactone is in turn prepared by decarboxylation of anu-carbo-lower-alkoxalyl-'y-butyrolactone by heating the latter in thepresence of sulfuric acid. The product isolated from the Fischer indolesynthesis described above generally consists of a mixture of the desired2-carboxy-3-(2-hydroxyethyl)indo1e and the lactone resulting fromesterification between the 2-carboxy and the 3-(2-hydroxyethyl)groups.It is therefore advantageous to reflux the crude product obtained in alower-alkanol in the presence of excess anhydrous hydrogen halide, whichresults in the transformation of both Fischer indole products to thedesired 2-carbo-lower-alkoxy-3-(2- haloethyl)indole of Formula II.

The compounds of Formula I where R is carboxy are prepared by alkalinehydrolysis of the corresponding compounds where R is carbo-lower-alkoxy.The reaction is preferably carried out either in an aqueous or anaqueous-alcoholic medium at the reflux temperature thereof and in thepresence of an alkali metal hydroxide. If desired, the compounds can beisolated from the alkaline reaction medium to produce the alkali metalsalts of the compounds where R is carboxy.

The compounds of Formula I where R is carbamyl, N-lower-alkylcarbamyl,or N,N-di-lower alkylcarbamyl, are prepared by reacting thecorresponding compounds where R is carboxy with a thionyl halide, eitherin the 3 absence of a solvent or in an inert organic solvent such asbenzene, toluene, or xylene, and reacting the resulting 2-haloformylcompound with, respectively, anhydrous ammonia, a lower-alkylamine [e.g.methylamine (CH NH ethylamine (C H NH or 2-pentylamine (CH CH CH CH(CH)NH or a di-lower-alkylamine {e.g. dimethylamine or methylpentylamine(CH NHC H The compounds of Formula I where R is hydroxymethyl areprepared by reducing the corresponding compounds where R is carboxy orcarbo-lower-alkoxy with an alkali metal aluminum hydride. The reactionis preferably carried out in an organic solvent inert under theconditions of the reaction, for example diethyl ether, tetrahydrofuran,dibutyl ether, and the like, at temperatures in the range from 0100 C.

The compounds of Formula I where R is hydroxymethyl can also be preparedby alkali metal aluminum hydride reduction, as described above, of a1-[(2-R -3- indolyl)acetyl] 4 substituted-piperazine having the formula:

CHzC ON N I where R R and Y have the meanings given above, and R iscarbo-loWer-alkoxy, carboxy, or hydroxymethyl.

The compounds of Formula I where R is lower-alkanoyl-oxymethyl areprepared by reacting the corresponding compounds where R ishydroxymethyl with a lower-alkanoyl halide in an organic solvent inertunder the conditions of the reaction, for example benzene, toluene,xylene, and the like, and in the presence of an acidacceptor, forexample pyridine, dimethylaniline, triethylamine, and the like, which isused to take up the hydrogen halide split out during the course of thereaction.

The compounds of Formula I where R is sulfo are prepared by reaction ofthe corresponding compounds where R is hydrogen with sodium bisulfite inan aqueous alcoholic medium at a pH of around 7.0. The reaction ispreferably carried out at room temperature while bub 'bling a current ofair through the mixture.

The compounds of Formula I where R is formyl are prepared by reducingthe corresponding compounds where R is haloformyl with tri-t-butoxylithium aluminum hydride in an organic solvent inert under theconditions of the reaction, for example diethyl ether, dibutyl ether, ortetrahydrofuran, at temperatures in the range from 0- 50 C.

The compounds of Formula I where R is isonitrosomethylene are preparedby reacting the corresponding compounds where R is formyl withhydroxylamine, preferably under slightly acidic conditions and in aloweralkanol solvent at the reflux temperature thereof.

The acid-addition salts of the bases herein described are the form inwhich the bases are most conveniently prepared for use. The acidmoieties or anions in these salt forms are in themselves neither novelnor critical and therefore can be any acid anion or acid-like substancecapable of salt formation with the free base form of the compounds. Thepreferred type of salts are watersoluble pharmacologically acceptablesalts, that is, salts whose anions are relatively innocuous to theanimal organisms in pharmacological doses of the salts, so that thebeneficial physiological properties inherent in the free base are notvitiated by side effects ascribable to the anions; in other words, thelatter do not substantially affect the pharmacological propertiesinherent in the cations. Appropriate pharmacologically acceptable saltswithin the scope of the invention are those derived from mineral acidssuch as hydrobromic acid, hydriodic acid, nitric acid, phosphoric acid,sulfamic acid, and sulfuric acid; and organic acids such as acetic acid,citric acid, tartaric acid, lactic acid, methanesulfonic acid,ethanesulfonic acid, quinic acid, and the like, giving the hydrobromide,hydriodide, nitrate, phosphate, sulfamate, sulfate, acetate, citrate,tartrate, lactate, methanesulfonate, ethanesulfonate and quinate,respectively.

Although pharmacologically acceptable salts are preferred, those havingtoxic anions are also useful. All acidaddition salts are usefulintermediates as sources of the free base form even if the particularsalt per se is not desired as the final product, as for example when thesalt is formed only for purposes of purification or identification, orwhen it is used as an intermediate in preparing a pharmacologicallyacceptable salt by ion-exchange procedures.

Pharmacological evaluation of the compounds of Formula I according tostandard pharmacological test procedures has demonstrated that theypossess psychomotor depressant activity thus indicating their usefulnessas tranquilizers.

Psychomotor depressant activity was determined in standard activitycages using the method of Dews, Brit. J. Pharmacol. 8, 46 (1953) inwhich mice, medicated with the test compound, are placed in wire meshcages equipped with a photoelectric cell so adjusted that a mousebreaking the beam activates a magnetic digital counter. Thus the numberof times the light beam is broken over a period of time is an indicationof the motor activity of the animals, and a reduction in the number ofcounts in the medicated mice over control groups run simultaneously, istaken as evidence of psychomotor depressant activity. The dose at whichsuch reduction in motor activity was observed was recorded as theactive-dose. Alternatively, the ED the Effective Dose in 50% of theanimals, was determined from a dose-response curve.

Instead of determining the motor activity of the test animals using adigital counter activated by a photoelectric cell, there can also beused a counting apparatus such as described by Bonta et al., Arch. int.pharmacodyn. 129, 381-394 (1960) in which vertically movable leafsprings affixed to the activity cages activate a direct current amperehour meter which serves as a counter of the recorded activity. Moreover,as these authors show, compounds which depress motor activity of mice insuch activity cages are indicated to possess tranquilizer activity.

The compounds of the invention, when administered orally to mice in theabove-described psychomotor activity test, were found to be active inthe dose range of from 8 to 300 mg./kg. of body weight.

The compounds can be prepared for use by dissolving under sterileconditions a salt form of the compounds in water (or an equivalentamount of a non-toxic acid if the free base is used), or in aphysiologically compatible aqueous medium such as saline, and stored inampoules for use by injection. Alternatively, they can be incorporatedin unit dosage form as tablets or capsules for oral administrationeither alone or in combination with suitable adjuvants such as calciumcarbonate, starch, lactose, talc, magnesium stearate, gum acacia, andthe like. Still further the compounds can be formulated for oraladministration in aqueous alcohol, glycol or oil solutions or oil-wateremulsions in the same manner as conventional medicinal substances areprepared.

The chemical structures of the compounds of the invention areestablished by their mode of synthesis and are corroboated by infraredand ultraviolet spectra, and by the correspondence between calculatedvalues for the elements and values found by chemical analysis.

The following examples will further illustrate specific; embodiments ofthe invention.

EXAMPLE 1 1-[2-(Z-carbethoxy-5,6-dimethoxy-3-indolyl)ethyl]-4-phenylpiperazine To a suspension of 23 g. (1.0 mole) of sodium pelletsin 800 ml. of absolute ether was added 80 ml. of a mixture of 86 g. 1.0mole) of 'y-butyrolactone and 146 g. (1.0 mole) of ethyl oxalate. Thereaction mixture began to boil gently and was allowed to refluxspontaneously for two hours, after which time the remainder of the'ybutyrolactone and ethyl oxalate mixture was added cautiously. Whenaddition was complete, the mixture was refluxed for one hour, allowed tostand overnight, and the ether removed in vacuo. The residue was mixedwith ice, acidified with cold, dilute sulfuric acid, extracted withether, and the ether extracts dried over sodium sulfate and taken todryness. Distillation of the residue in vacuo at 0.05 mm. afforded 98 g.of tx-ethoxalyl-' -butyrolactone, collected between 110126 C.

Forty grams (0.215 mole) of the latter were heated under reflux in 100ml. of 2 N sulfuric acid until the evolution of carbon dioxide ceased,giving a solution of a-keto-a-valerolactone.

3,4-dimethoxyphenylhydrazine hydrochloride (44 g., 0.22 mole) wasdissolved in 300 ml. of water, treated with a solution of 12.3 g. (0.22mole) of potassium hydroxide in 50 ml. of water, and cooled. To thismixture was added the abovedescribed solution of a-keto 8-valerolactone, and the pH of the mixture was adjusted to about 2 with10% sodium hydroxide. The mixture was warmed on a hot plate for fiveminutes, allowed to cool, extracted with chloroform, and the extractsdried over magnesium sulfate and concentrated to dryness giving 66 g. ofcrude hydrazone.

The latter was dissolved in 100 ml. of absolute ethanol, the mixtureacidified with 400 ml. of saturated ethanolic hydrogen chloride, and astream of hydrogen chloride gas was passed through the mixture causingthe temperature to rise to 80 C. The solid which separated from thereaction mixture was collected after standing overnight, and washed withcold absolute ethanol to give 38 g. of crude 2-carboxy-5,6 dimethoxy 3(2hydroxyethyl)-indole.

The latter was suspended in 300 ml. of absolute ethanol and the solutionsaturated with anhydrous hydrogen chloride for one hour. The mixture wasallowed to stand for two hours, and the solid which separated wascollected and dried to give 24 g. of Z-carbethoxy 5,6-dimethoxy-3-(2-chloroethyl)indole, M.P. 179-181 C.

The latter was added to 15 ml. of l-phenylpiperazine and the mixtureheated at 140-160 C. for one hour and twenty minutes. The cooled mixturewas triturated with 100 ml. of ether, filtered, and the ether filtrateconcentrated to dryness. The residue was mixed with water and aceticacid, the pH adjusted to about 5.0, and the insoluble material wascollected by filtration giving g. of crude product which wasrecrystallized from methanol to give 2.2 g. of 1-[2-(2 carbethoxy-5,6dimethoxy- 3-indolyl)ethyl] 4 phenylpiperazine, M.P. 142.5144.0 C.

EXAMPLE 2 By reacting an appropriate 2-carbo-lower-alkoxy 3-(2-chloroethyl)indole with an appropriate l-substitutedpiperazine, usingthe procedure described above in Example 1, there are obtained thefollowing compounds of Formula I:

(A) 1-[2-(Z-carbethoxy-S,6-dimethoxy 3 indolyl)- ethyl]-4-(2methoxyphenyl)piperazine hydrochloride, M.P. 272274 C. prepared from1-(2-methoxy henyl)- piperazine and Z-carbethoxy 5,6dimethoxy-3-(2-chloroethyl)indole;

(B) 1-[2 (2 carbethoxy 5 ethoxy-6-methoxy- 3-indolyl)ethyl] 4(4-methoxyphenyl)piperazine, prepared from 1 (4 methoxyphenyl)piperazineand 2- carbethoxy 5 ethoxy 6 methoxy-3-(2-chloroethyl)- indole, thelatter being prepared from 3-ethoxy-4-methoxyphenylhydrazine andu-keto-6-valerolactone and reaction of the crude product with ethanolichydrogen chloride, all according to the procedure described above inExample 1;

(C) 1-[2-(2 carbethoxy 4 methoxy-3-indolyl)- ethyl] 4(4-chlorophenyl)piperazine, prepared from 1-(4-chlorophenyl)piperazineand 2 carbethoxy 4- methoxy-3-(2-chloroethyl)indole, the latter beingprepared by reaction of 3-methoxyphenylhydrazine and onketofi-valerolactone and reaction of the crude product with ethanolichydrogen chloride, all according to the procedure described above inExample 1;

(D) 1-[2-(2 carbethoxy 7 methoxy-3-ind0lyl)- ethyl] 4(3,4-dimethoxyphenyl)piperazine, prepared from 1(3,4-dimethoxyphenyl)piperazine and 2-carbethoxy 7 methoxy 3 (2chloroethyl)indole, the latter being prepared from2methoxyphenylhydrazine and a-keto-5-valerolactone and reaction of thecrude product with ethanolic hydrogen chloride, all according to theprocedure described above in Example 1;

(E) 1-[2 (2-carbethoxy 5 methyl-3-indolyl)ethyl]- 4-(2 methoxy 5chlorophenyl)piperazine, prepared from 1-(2 methoxy 5chlorophenyl)piperazine and 2 carbethoxy 5methyl-3-(2-chloroethyl)indole, the latter being prepared from4-methylphenylhydrazine and a-keto-avalerolactone and reaction of thecrude product with ethanolic hydrogen chloride, all according to theprocedure described above in Example 1;

(F) 1-[2 (2 carbethoxy 4 chloro-3-indolyl)ethyl]- 4-(2 methyl 3chlorophenyl)piperazine, prepared from 1-(2-methyl 3chlorophenyl)piperazine and 2- carbethoxy 4 chloro 3(2-chloroethyl)indole, the latter being prepared from3-chlorophenylhydrazine and a-keto-fi-valerolactone and reaction of thecrude product with ethanolic hydrogen chloride, all according to theprocedure described above in Example 1;

(G) 1-[2-(2-carbethoxy S-fluoro 3-indolyl)ethyl]-4-(3-methylphenyl)piperazine, prepared from 1-(3-methylphenyl)-piperazineand Z-carbethoxy 5-fluoro-3-(2-chloroethyl)indole, the latter beingprepared from 4-fluorophenylhydrazine and a-keto-fi-valerolactone andreaction of the crude product with ethanolic hydrogen chloride, allaccording to the procedure described above in Example 1;

(H) 1-[2-(2-carbethoxy-5,6-methylenedioxy-3-indolyl)-ethyl]-4-(2,6-dimethylphenyl)piperazine, prepared from1-(2,6-dimethylphenyl)piperazine and 2-carbethoxy-5,6-methylenedioxy-3-(2-chloroethyl)indole, the latter being prepared byreaction of 3,4-mcthylenedioxyphenylhydrazine withoc-k6tO-d-VH16YO1QCIOI1E and reaction of the crude product withethanolic hydrogen chloride, all according to the procedure describedabove in Example 1;

(I) 1-[2-(2-carbethoxy 5,6-ethylenedioxy 3-indolyl)-ethyl]-4-(4-fluorophenyl)piperazine, prepared from 1-(4-fluorophenyl)piperazine and 2-carbethoxy-5,6-ethylenedioxy3-(2-chloroethyl)indole, the latter being prepared by reaction of3,4-ethylenedioxyphenylhydrazine with ot-keto- 8-valerolactone andreaction of the crude product with ethanolic hydrogen chloride, allaccording to the procedure described above in Example 1;

(I) 1-[2-(2-carbethoxy S-benzyloxy 3-indolyl)ethyl -4-3-trifluoromethylphenyl piperazine, prepared from1-(3-trifluoromethylphenyl)piperazine and Z-carbethoxy-5-benzyloxy-3-(2-chloroethyl)indole, the latter being prepared byreaction of 4-benzyloxyphenylhydrazine with 0:- keto-fiwalerolactone andreaction of the crude product with ethanolic hydrogen chloride, allaccording to the procedure described above in Example 1;

(K) 1-[2-(2-carbethoxy S-hydroxy 3-indolyl)ethyl]-4-(Z-methylmercaptophenyl)piperazine, prepared from 1-(2-methylmercaptophenyl)piperazine and 2-carbethoxy- S-hydroxy3-(2-chloroethyl)indole, the latter being prepared by reaction of4-hydroxyphenylhydrazine with aketo-a-valerolactone and reaction of thecrude product with ethanolic hydrogen chloride, all according to theprocedure described above in Example 1;

(L) 1-[2-(2-carbethoxy -methylmercapto-3-indolyl)-ethlyl]-4-methylpiperazine, prepared from l-methylpiperazine and2-carbethoxy 5-methylmercapto-3-(2-chlor0- ethyl)indole, the latterbeing prepared by reaction of 4-methylmercaptophenylhydrazine withOL-ktO--VEI1CTO- lactone and reaction of the crude product Withethanolic hydrogen chloride, all according to the procedure describedabove in Example 1;

(M) 1-[2-(2-carbethoxy 6-ch1oro 7-methyl 3-indolyl)-ethyl] 4-(2hydroxyethyl)piperazine, prepared from 1-(2-hydroxyethyl)piperazine and2-carbethoxy-6- chloro 7-methyl 3-(2-chloroethyl)indole, the latterbeing prepared by reaction of 2-methyl-3-chlorophenylhydrazine witha-keto-rS-valerolactone and reaction of the crude product with ethanolichydrogen chloride, all according to the procedure described above inExample 1;

(N) 1-[2-(2-carbethoxy5,6-dimethoxy-3-indolyl)ethyl]-4-(2-pyridyl)piperazine, prepared fromI-(Z-pyridyl) piperazine and 2-carbethoxy 5,6-dimethoxy3(2-chloroethyl)indole;

O) 1-[2-(2-carbethoxy 5,6-dimethoxy 3-indolyl) ethyl]4-(Z-pyrimidyDpiperazine, prepared from 1-(2- pyrimidyl)piperazine and2-carbethoxy 5,6-dimethoxy- 3-(2-chloroethyl)indole;

(P) 1-[2-(2-carbethoxy 5,6 dimethoxy 3-indolyl)ethyl]-4-(2-phenylethyl)piperazine, prepared from 1-(2-phenylethyDpiperazine and Z-carbethoxy 5,6-dimethoxy-3-(2-chloroethyl)indole;

(Q) 1-[2-(2-carbethoxy 5,6-dimethoxy 3-indolyl)ethyl]-4-cinnamylpiperazine, prepared from l-cinnarnylpiperazine and2-carbethoxy 5,6 dimethoxy 3-(2- chloroethyl)indole;

(R) 1-[2-(2-carbopropoxy 5,6-dimethoxy 3-indolyl)-ethyl]-4-phenylpiperazine, M.P. 159-161 0, prepared by reaction ofl-phenylpiperazine with 2-carbopropoxy-5,6- dimethoxy3-(2-chloroethyl)indole, M.P. 185186.5 C., the latter being prepared byreaction of 3,4-dimethoxyphenylhydrazine with a-keto-a-valerolactone andreaction of the resulting product with anhydrous hydrogen chloride inabsolute propanol;

(S) 1-[2-(2-carbomethoxy 5,6-dimethoxy 3-indolyl) ethyl]4-phenylpiperazine, M.P. 156l58 C., prepared from l-phenylpiperazine and2-carbomethoxy 5,6-dimethoxy 3-(2-chloroethyl)indole, the latterprepared by reaction of 3,4-dimethoxyphenylhydrazine witha-keto-fivalerolactone and reaction of the crude product with methanolichydrogen chloride;

(T) 1-[2-(2-carbethoxy 5,6-dimethoxy 3-indolyl)-ethyl]-4-(4-hydroxyphenyl)piperazine, M.P. 16l-166 C. (uncorr.),prepared from 1-(4-hydroxyphenyl)piperazine and2-carbethoxy-5,6-dimethoxy-3-(2-chloroethyl)indole;

(U) 1-[2-(2-carbethoxy 5-methylsulfonyl 3-indolyl)-ethyl]-4-(4-pyridyl)piperazine, prepared from 1-(4-pyridyl)-piperazineand Z-carbethoxy 5-methylsulfonyl-3-(2- chloroethyl)-indole, the latterprepared by reaction of 4- methylsulfonylphenylhydrazine witha-keto-a-valerolactone and reaction of the crude product with ethanolichydrogen chloride;

(V) l-[2-(2-carbethoxy 5-trifluorornethyl 3-indolyl)- ethyl] 4-(4methylsulfinylphenyl)piperazine, prepared froml-(4-methylsulfinylphenyl)piperazine and 2-carbethoxy 5-trifluoromethyl3-(2 chloroethyl)indole, the latter prepared by reaction of4-trifiuoromethylphenylhydrazine with a-keto-fi-valerolactone andreaction of the crude product With ethanolic hydrogen chloride;

(W) 1-[2-(2-carbethoxy S-methylsulfinyl 3-indolyl)- ethyl]4-(4-rnethylsulfonylphenyl)piperazine, prepared from 1-(4methylsulfonylphenyl)piperazine and 2-carbethoxy S-methylsulfinyl3-(2-chloroethyl)indole, the latter prepared by reaction of4-methylsulfinylphenylhydrazine with u-keto-6-valerolactone and reactionof the crude product With ethanolic hydrogen chloride;

(X) 1-[2-(2-carbethoxy 3-indolyl)ethyl]-4-(3,4-methylenedioxyphenyl)piperazine, prepared from1-(3,4-methylene-dioxyphenyl)piperazine and 2 carbethoxy 3-(2-ehl0roethyl)indole; and

8 (Y) 1-[2-(2-carbethoxy3-indolyl)ethyl]-4-(3,4-ethylenedioxyphenyl)piperazine, prepared from1-(3,4-ethylenedioxyphenyl)piperazine and Z-carbethoxy3-(2-chloroethyl)indole.

EXAMPLE 3 1-[2- (2-carboxy-5,6-dimethoxy-3 -indolyl)ethyl]4-phenylpiperazine A mixture of 1.1 g. (0.0027 mole) of1-[2-(2-carbethoxy-5,6-dimethoxy 3 indolyl)ethyl] 4 phenylpiperazine, in10 ml. of 10% sodium hydroxide and 10 ml. of a 1:1 mixture of ethanoland water was heated under reflux for ten minutes, allowed to stand forthirty minutes, poured into water and ice, acidified with dilutehydrochloric acid, and the solid which separated was collected, washedwith water, dried and recrystallized from 50% aqueous ethanol, giving0.5 g. of 1-[2-(2-carboxy- 5,6 dimethoxy 3indolyl)ethyl]-4-phenylpipera2ine, M.P. 173176 C.

The latter was converted to its 2-potassium carboxylate salt bydissolving 3.1 g. (0.008 mole) of the acid in a solution containing 425mg. of potassium hydroxide in absolute ethanol, and recovering the saltfrom the cooled, concentrated mixture. The crude product wasrecrystallized from an ethyl acetate/ether mixture to give 3.5 g of thepotassium salt.

EXAMPLE 4 By hydrolyzing the compounds described above in Examples 2A-2Qand 2T-2Y with aqueous ethanolic sodium hydroxide, using the proceduredescribed above in Example 3, there can be obtained the respectivecompounds of Formula I below where R in each instance, is COOH:

(A) 1-[2-(2 carboxy 5,6 dimethoxy-3-indolyl)-ethyl]-4-(Z-methoxyphenyl)piperazine;

(B) 1-[2-(2 carboxy 5 ethoxy 6-methoxy-3- indoly1)-ethyl]-4-(4-methoxyphenyl)piperazine;

(C) 1-[2-(2 carboxy 4 methoxy-3-indoyl)ethyl]-4-(4-chlorophenyl)piperazine;

(D) 1-[2-(2-carboxy 7 methoxy 3-indolyl)ethyl]-4-(3,4-dimethoxyphenyl)piperazine;

(E) 1-[2-(2-carboxy 5 methyl 3 indolyl)ethy1]-4-(2-rnethoxy-5-chlorophenyl)piperazine;

(F) 1-[2-(2-carboxy-4-chloro 3 indoly1)ethyl]-4- 2-methyl-3-chlorophenyl) piperazine;

(G) 1-[2-(2-carboxy 5 fiuoro 3 indolyl)ethyl]-4-(3-methylpheny1)piperazine;

(H) 1-[2-(2-carboxy 5,6 methylenedioxy-3-indolyl)-ethyl]-4-(2,6-dimethylpheny1)piperazine;

(I) 1-[2-(2-carboxy-5,6-ethylenedi0xy 3 indolyl)ethyl]-4-(4-fluorophenyl)piperazine;

(J) 1-[2-(2-carboxy-5-benzyloxy-3-indolyl)ethyl] 4-(3-trifluoromethylphenyl) piperazine;

(K) 1-[2-(2-carboxy 5 hydroxy 3-indolyl)ethy1]-4-(Z-methylmercaptophenyl)piperazine;

(L) 1- [Z-(Z-carboxy 5 methylmercapto 3-indoly1)- ethyl]-4-methylpiperazine;

(M) 1-[2-(2-carboxy 6 chloro-7-methy1 3-indolyl)-ethyl]-4-(Z-hydroxyethyl)piperazine;

(N) 1[2-(2-carboxy 5,6 dimethoxy 3-indolyl)- ethyl] -4 (2-pyridylpiperazine;

(O) 1-[2-(2-carboxy 5,6-dimethoxy-3-indolyl)ethyl]-4-(2-pyrimidyl)piperazine;

(P) 1-[2-(2-carboxy 5,6-dimethoxy 3 indolyl)- ethyl] -4- (2-phenylethyl)piperazine;

(Q) 1-[2-(2-carboxy 5,6-dimethoxy-3-indolyl)ethyl]-4-cinnamylpiperazine;

(R) 1-[2-(2-carboxy-5,6-dirnethoxy 3-indolyl)ethyl]- 4- (4-hydroxyphenylpiperazine;

(S) 1-[2-(2-carboxy 5 methylsulfonyl 3-indolyl)-ethyl]=4-(4-pyridyl)piperazine;

(T) 1-[2-(2-carboxy 5 trifluoromethyl-3-indolyl)- ethyl] -4-(4-methylsulfinylphenyl) piperazine;

(U) 1-[2-(2-carboxy methylsulfinyl 3-indolyl)- ethyl]-4-(4-methylsulfony1pheny1)piperazine;

(V) l-[2-(2-carboxy 3indolyl)-ethyl]-4-(3,4-methylenedioxyphenyl)piperazine; and

(W)1-[2-(2-carboxy-3-indolyl)ethyl]-4-(3,4-ethylenedioxyphenyl)piperazine.

EXAMPLE 5 1- [2-(2-hydroxymethyl-5,6-dimethoxy-3-indolyl)ethyl]-4-phenylpiperazine A solution of 9.3 g. (0.021 mole) of1-[2-(2-carbethoxy 5,6 dimethoxy 3 indolyl)ethyl] 4 phenylpiperazine, in100 ml. of tetrahydrofuran was added with stirring to a slurry of 2.0 g.(0.054 mole) of lithium aluminum hydride in 250 ml. of tetrahydrofuran.The mixture was stirred at room temperature for thirty minutes,decomposed with water, filtered, the filter washed with tetrahydrofuran,and the combined filtrates taken to dryness in vacuo giving 8.5 g. of awhite solid which was recrystallized from methanol to give 6.6 g. of1-[2- (Z-hydroxy-methyl 5,6 dimethoXy 3-indolyl)ethyl]-4-phenylpiperazine, M.P. l65168 C.

EXAMPLE 6 By reduction of the compounds described above in Examples2A-2Q and 2T-2Y with lithium aluminum hydride, using the proceduredescribed above in Example 5, there can be obtained the followingrespective compounds of Formula I where R in each instance, is CHQOHZ(A) l-[2-(2-hydroxymethyl 5,6dimethoxy-3-indolyl)ethyl]-4-(2-methoxyphenyl)piperazine, M.P. 170- 172C.;

(B) 1-[2-(2-hydroxymethyl 5 ethoxy 6-methoxy-3-indolyl)ethyl]-4-(4-methoxyphenyl)piperazine;

(C) 1-[2-(2-hydroxymethyl 4 methoxy 3 indolyl)ethyl]-4-(4-chlor0phenyl)piperazine;

(D) l-[2-(2 hydroxymethyl 7 methoXy-3-indolyl)ethyl]-4-(3,4-dimethoXyphenyDpiperazine;

(E) 1 [2-(2-hydroxymethyl 5 methyl-3-indolyl) ethyl] -4-2-methoxy-5-chlorophenyl) piperazine;

(F) 1-[2-(2-hydroxymethyl 4 chloro 3 indolyl)ethyl]-4-(2-methyl-3-chlorophenyl)piperazine;

(G) l-[2-(2-hydroxymethyl 5 fluoro 3 indolyl)ethyl]-4-(3-methylphenyl)piperazine;

(H) l-[2-(2-hydroxymethyl 5,6 methylenedioxy-3- indolyl) ethyl] -4-2,6-dimethylphenyl piperazine;

(I) 1-[2-(2-hydroxymethyl 5,6 ethylenedioxy-3-indolyl ethyl] -4-4-fluoropheny1 piperazine;

(J 1-[2-(2-hydroxymethyl 5 benzyloxy 3-indoly ethyl] -4-3-trifluoromethylphenyl piperazine;

(K) l-[2-(2-hydroxymethyl 5 hydroxy-3-indolyl) ethyl] -4-2-methylmercaptophenyl piperazine;

(L) l-[2-(2-hydroxymethyl 5 methylcercapto-3-indolyl) ethyl]-4-methylpiperaziue;

(M) l-[2-(2-hydroxymethyl 6 chloro-7-methyl-3- indolyl ethyl] -4-2-hydroxyethyl) piperazine;

(N) l-[2-(2-hydroxymethyl 5,6 dimethoxy-3-indolyl ethyl] -4- 2-pyridyl)piperazine;

(O) l-[2-(2-hydroxymethyl 5,6 dimethoxy-3-indolyl ethyl] -4- Z-pyrimidylpiperazine;

(P) l-[2-(2-hyd1'oxymethyl 5,6 dimethoxy-3-indolyl ethyl] -4-Z-phenylethyl piperazine;

(Q) l-[2-(2-hydroxymethyl 5,6dimethoxy-3-indolyl)ethyl]-4-cinnamylpiperazine;

(R) 1-[2-(2-hydroxymethyl 5,6 dimethoxy-3-indolyl) ethyl] -4-(4-hydroxyphenyl) piperazine;

(S) l-[2-(2-hydroxymethyl 5 methylsulfonyl-S-indolyl ethyl] -4-(4-pyridyl piperazine;

(T) 1-[2-(2-hydroxymethyl 5 trifluoromethyl-3-indolyl ethyl] -4-(4-methylsulfinylphenyl) piperazine;

(U) l-[2-(2-hydroxymethyl 5 methylsulfinyl 3indolyl)ethyl]-4-(4-methylsu1fonylphenyl)piperazine;

(V) 1-[2-(2-hydroxymethyl 3 indolyl)ethyl]-4-(3,4-methylenedioxyphenyl)piperazine; and

10 (W) 1-[2-(2-hydroxymethyl 3 indolyl)ethyl]-4-(3,4-ethylenedioxyphenyl piperazine.

EXAMPLE 7 l-[2-(2-acetoxymethyl 5,6 dimethoxy-3-indolyl)ethyl]4-pheny1piperazine By reaction of 1-[2-(Z-hydroxymethyl-S,6-dimethoxy-3-indolyl)ethyl]-4-phenylpiperazine with acetyl chloride in the presenceof pyridine, there can be obtained 1-[2-(2- acetoxymethyl 5,6 dimethoxy3 indolyl)ethyl]-4- phenylpiperazine.

EXAMPLE 8 By reaction of the compounds described above in Example 6 withacetyl chloride in the presence of pyridine, using the proceduredescribed above in Example 7, there can be obtained the followingrespective compounds of Formula I where R in each instance, is CH OCOCH(A) l-[2-(2-acetoxymethyl 5,6 dimethoxy-3-indolyl) ethyl] -4-(Z-methoxyphenyl piperazine;

(B) l-[2-(2-acetoxymethyl 5 ethoxy-6-methoxy-3- indolyl) ethyl] -4-(4-rnethoxyphenyl piperazine;

(C) l-[2-(2-acetoxymethyl 4 methoxy-3-indolyl)ethyl]-4-(4-chlorophenyl)piperazine;

(D) 1-[2-(2-acet0xymethyl 7 methoxy-3-indolyl) ethyl] -4- (3,4-dimethoxyphenyl) piperazine;

(E) 1-[2-(2-acetoxymethyl 5 methyl 3 indolyl) ethyl] -4-2-methoxy-5-chlorophenyl piperazine;

(F) l-[2-(2-acetoxymethyl 4 chloro 3 indolyl) ethyl] -4- 2-methyl-3-chlorophenyl piperazine;

(G) 1-[2-(2-acetoxymethyl 5 fluoro 3 indolyl) ethyl -4- 3 -methylphenyl)piperazine;

(H) l-[2-(2-acetoxymethyl 5,6 methylenedioxy-3- indolyl)ethyl] 4(2,6-dimethylphenyl)piperazine;

(I) l-[2-(2-acetoxymethyl 5,6 ethylenedioxy-3-indolyl ethyl] -4-(4-fiuorophenyl piperazine;

(l) l-[2-(2-acetoxymethyl 5 benzyloxy-3-indolyl) ethyl] -4-3-trifiuoromethylphenyl) piperazine;

(K) l[2-(2-acetoxymethyl 5 hydroxy-3-indolyl)ethyl)-4-(2-methylmercaptophenyl)piperazine;

(L) l-[2-(2-aeetoxymethyl 5 methylmercapto-Ya-indolyl ethyl]-4-methy1piperazine;

(M) 1-[2-(2-acetoxymethyl 6 chloro-7-methyl-3-indolyl ethyl] -4-2-hydroxyethyl piperazine;

(N) 1-[2-(2-acetoxymethyl 5,6 dimethoxy-3-indolyl ethyl] -4- 2-pyridylpiperazine;

(O) 1-[2-(2-acetoxymethyl 5,6 dimethoXy-3-indolyl ethyl] -4-2-pyrimidy1) piperazine;

(P) 1-[2-(2-acetoxymethyl 5,6 dimethoxy-3-indolyl ethyl] -4-(2-phenylethyl piperazine;

(Q) l-[2-(2-acetoxymethyl 5,6dimethoxy-3-indolyl)ethyl]-4-cinnamylpiperazine;

(R) l-[2-(2-acetoxymethyl 5,6 dimethoxy-3-indolyl ethyl] -4-4-hydroxyphenyl piperazine;

(S) 1-[2-(2-acetoxymethyl 5 methylsulfonyl-3-indolyl ethyl] -4-4-pyridyl piperazine;

(T) 1-[2-(2-acetoxymethyl 5 trifiuoromethyl-3-indolyl) ethyl] -4-4-methylsulfinylphenyl piperazine;

(U) 1-[2-(2-acetoxymethyl 5methylsulfinyl-3-indolyl)ethyl]-4-(4-methylsulfonylphenyl)piperazine;

(V) 1-[2-(2-acetoxymethyl 3 indolyl)ethyl]-4-(3,4- methylenedioxyphenylpiperazine; and

- (W) 1-[2-(2-acetoxymethyl 3 ind0lyl)ethyl]-4-(3,4-ethylenedioxyphenyl)piperazine.

EXAMPLE 9 1- 2- 2-formyl-5,6-dimethoxy-3 -indolyl) ethyl] -4-phenylpiperazine By reaction of l-[2-(2-carboxy 5,6dimethoxy-3-indolyl)ethyl]-4-phenylpiperazine with thionyl chloride inan organic solvent, for example toluene, and reduction of the resulting1-[2-(Z-chloroformyl-S,6-dimethoxy-3-indolyl)ethyl]-4-phenylpiperazinewith tri-t-butoxy lithium aluminum hydride, there can be obtained1-[2-(2-formyl- 5,6-dimethoxy-3-indolyl) ethyl] -4-phenylpiperazine.

1 1 EXAMPLE 10 By reaction of the compounds described above in Example 4with thionyl chloride, and reduction of the resulting 2-chloroforrnylcompounds with tri-t-butoxy lithium aluminum hydride, all according tothe procedure de scribed above in Example 9, there can be obtained thefollowing respective compounds of Formula I where R in each instance, isCHO:

(A) 1 [2-(2-formyl-5,6-dimethoxy-3-indolyl)-ethyl]- 4- (Z-methoxyphenyl)piperazine (B) 1-[2-(2-formyl-5-ethoxy-6-methoxy 3 indolyl)-ethyl]-4-(4-methoxyphenyl)piperazine;

(C) 1-[2-(2-formyl-4-methoxy 3 indoly1)ethyl]-4- (4-chlorophenyl)piperazine;

(D) 1 [2 (2-formyl-7-methoxy-3-indolyl)ethyl]-4-(3,4-dimethoxyphenyl)piperazine;

(E) 1-[2-(2 formyl 5-methyl-3-indolyl)ethyl]-4-(2-methoxy-S-chlorophenyl)piperazine;

(F) 1-[2-(2-formyl 4 chloro-3-indolyl)ethyl]-4-(2- methyl-3-chl0rophenylpiperazine (G) 1-[2-(2-formyl-5-fiuoro 3 indolyl)ethyl]-4-(3-methylphenyl)piperazine;

(H) 1-[2-(2-formyl-5,6-methylenedioxy 3 indolyl)- ethyl] -4-(2,6-dimethylphenyl pip erazine;

(I) 1-[2-(2 formyl 5,6 ethylenedioxy-3-indolyl)-ethyl]-4-(4-fluorophenyl)piperazine;

(J) 1-[2-(2-formyl 5 benzyloxy-3-indoly1)ethyl]4-(3-trifluoromethylphenyl) piperazine.

(K) l-[2-(2-formyl-5-hydroxy 3 indoly1)ethyl]-4(Z-methylmercaptophenyl)piperazine;

(L) 1- [2 (2 formyl-S-methylmercapto-3-indolyl) ethyl]-4-methylpiperazine;

(M) 1-[2-(2-formyl 6 chloro-7-methyl-3-indolyl)- ethyl] -4-(2-hydroxyethyl) piperazine;

' (N) 1- [2-(2-formy1-5,6-dimethoxy-3-indolyl)ethyl]-4- (2-pyridylpiperazine;

(O) 1-[2-(2-formyl-5,6-dimethoxy 3 indolyl)ethyl]-4-(2-pyrimidyl)piperazine;

(P) 1-[2-(2-formy1 5,6-dimethoxy 3-indolyl)ethyl]-4-(Z-phenylethyl)piperazine;

(Q) 1-[2-(2 formyl 5,6-dimethoxy-3-indolyl)ethyl]- 4-cinnamylpiperazine;

(R) 1-[2 (2. formyl-S,6-dimethoxy-3-indolyl)ethyl]- 4- (4-hydroxyphenylpiperazine;

(S) 1-[2-(2-formyl 5 methylsulfonyl-S-indolyl)ethyl] -4-(4pyridylpiperazine;

(T) 1-[2-(2 formyl 5 trifluoromethyl-3-indolyl) ethyl] -4-(4-methylsulfinylphenyl piperazine;

(-U) 1- [2- (2-formyl-5-methylsulfinyl-3-indolyl) ethyl] 4-(4-methylsulfonylphenyl piperazine;

(V) l-[2-(2-formyl 3indolyl)ethyl]-4-(3,4-methylenedioxyphenyl)piperazine; and

(W) 1-[2-(2-formyl-3-indolyl)ethyl]4-(3,4-ethylenedioxyphenyl)piperazine.

EXAMPLE 11 1- [2- (2-isonitrosomethylene-5 ,6-dimethoxy-3-indolyl)ethyl] -4-phenylpiperazine By reaction of1-[2-(2-formyl-5,6-dimethoxy-3-indolyl) ethyl]-4-phenylpiperazine withhydroxylamine in ethanol in the presence of a small amount ofhydrochloric acid, there can be obtained1-[2-(2-isonitrosomethylene-5,6-dimethoxy-3-indolyl)ethyl]-4-phenylpiperazine.

EXAMPLE 12 By reaction of the compounds described above in Example withhydroxylamine, using the procedure described above in Example 11, therecan be obtained the vfollowing respective compounds of Formula I where R(C) l-[2-(2-isonitrosomethylene 4 methoxy-3-indolyl) ethyl] -4-(4-chlorophenyl piperazine;

(D) 1-[2 (2 isonitrosomethylene-7-methoxy-3-indolyl) ethyl] -4-3,4-din1ethoxyphenyl piperazine (E) 1-[2-(2-isonitrosomethylene 5methyl3-indolyl ethyl] -4- (2-methoxy-5-chlorophenyl piperazine;

(F) 1-[2 (2-isonitrosomethylene-4-chloro-3-indolyl)- ethyl] -4-(2-methyl-3-chlorophenyl piperazine;

(G) 1-[2 (2-isonitrosomethylene-5-fluoro-3-indolyl)- ethyl] -4-3-rnethylphenyl piperazine;

(H) l- [2- (2-isonitrosomethylene-5,6-methylenedioxy- 3-indolyl) ethyl]-4- (2,6-dimethylphenyl) piperazine;

(I) 1-[2-(2 isonitrosornethylene-5,6-ethylenedioxy-3- indolyl ethyl] -4-(4-fluorophenyl piperazine;

(J) 1 [2 (2-isonitrosomethylene-S-benzyloxy-3-indolyl) ethyl] -4-3-trifluoromethylphenyl piperazine;

(K) 1 [2 (2-isonitrosomethylene-5-hydroxy-3-indolyl ethyl] -4-(Z-methylmercaptophenyl piperazine;

(L) 1-[2-(2. isonitrosomethylene-S-methylmercapto-3-indolyl)ethyl]-4-methylpiperazine;

(M) l-[2-(2-isonitrosomethylene 6 chloro-7-methyl- 3-indolyl ethyl] -4-(2-hydroxyethyl) piperazine;

(N) 1-[2 (2 isonitrosomethylene-S,6-dimethoxy-3- indolyl) ethyl] -4-(Z-pyridyl piperazine;

(O) l-[2-(2-isonitrosomethylene 5,6 dimethoxy-3-indolyl)ethyl]-4-(2-pyrimidyl)piperazine;

(P) l-[2-(2-isonitrosomethylene 5,6 dimeth0xy-3- indolyl ethyl] -4-2-phenylethyl piperazine;

(Q) 1-[2-(2 isonitrosomethylene 5,6-dimethoxy-3-indolyl)ethyl]-4-cinnamylpiperazine;

(R) 1-[2-(2-isonitrosomethylene 5,6 dimethoxy-3- indolyl) ethyl] -4-(4-hydroxyphenyl piperazine;

(S) 1 [2 (2-isonitrosomethylene-S-methylsulfony1- 3-indolyl) ethyl] -4-4-pyridyl piperazine;

(T) 1-[2-isonitrosomethylene 5 trifluoromethyl-3- indolyl ethyl] -4-(4-methylsulfinylphenyl piperazine;

(U) 1-[2-(2-isonitrosomethylene 5 methylsulfinyl-3- indolyl ethyl] -4-4-methylsulfonylphenyl) piperazine (V) 1-[2 (2isonitrosomethylene-3-indolyl)ethyl]- 4- 3 ,4-methylenedioxyphenyl)piperazine; and

(W) 1 [2-(2-isonitrosomethylene-3-indolyl)ethyl]-4-(3,4-ethylenedioxyphenyl)piperazine.

EXAMPLE 13 1- [2-(2carbamyl5,6-dimethoxy-3-indolyl) ethyl]-4-phenylpiperazine By reaction of 1- [2(2-carboxy-S,6-dimethoxy-3-indolyl)ethyl]-4-phenylpiperazine withthionyl chloride in toluene, and reacting the resulting 2-chloroformylcompound with anhydrous ammonia, there can be obtained 1-[2 (2carbamyl-5,6 dimethoxy-3-indolyl)ethyl]-4- phenylpiperazine.

EXAMPLE 14 By reacting the compounds described above in Example 4 withthionyl chloride, and reacting the resulting 2- chloroformyl compoundswith anhydrous ammonia, N- methylamine, or N,N-dirnethylamine, allaccording to the procedure described above in Example 13, there can beobtained the following respective compounds of Formula I where R iscarbamyl (CONH N-methylcarbamyl (CONHCH or N,N-dimethylcarbamyl [CON(CH(A) 1 [2-(2-carbamyl-5,6-dimethoxy3-indolyl)ethyl]-4-(Z-methoxyphenyl)piperazine (R is CONH (B) 1-{2- [2- N-methylcarbamyl)-5-ethoxy-6-methoxy- 3 indolyl]ethyl} 4-(4-methoxyphenyl)piperazine R isCONHCH (C) 1 {2 [2-(N,N-dimethylcarbamyl)-4-methoxy-3- indolyl]ethyl} 4(4 chlorophenybpiperazine [R is a)2];

(D) l [2 (2-carbamyl-7-methoxy-3-indolyl)ethyl]-4-(3,4-dimethoxyphenyl)piperazine (R is CONH (E)1-{2-[Z-(N-methylcarbamyl)-5-methyl-3-indolyl]- 13 ethyl} 4 (2methoxy-S-chlorophenyl)piperazine (R is CONHCH (F) 1 {2 [2(N,N-dirnethylcarbamyl)-4-ch10ro-3-indolyl]ethyl}-4-(2-methyl-3-chlorophenyl)piperazine [R is CON(CH (G) l[2-(2-carbamyl-5-flu0ro-3-indolyl)ethyl]-4-(3 methylphenyl)piperazine (Ris CONH (H) 1-{2-[2-(N-methylcarbamyl)5,6-methylenedi0Xy-3-indolyl]ethyl}-4-(2,6-dimethylphenyl)piperazine (R is CONHCH (I) l {2[2 (N,Ndimethylcarbamyl)-5,6-ethylenedioxy-3-indolyl]ethyl}-4-(4-fiuorophenyl)piperazineR is a)2];

(J 1 [2-(2-carbamyl-5-benzyloxy-3-indolyl)ethyl]-4-(3-trifluoromethylphenyl)piperazine (R is CONH '(K) l- {2 [2 (Nmethylcarbamyl) hydroxy-3- indolyl] ethyl}-4- 2-methylmercaptophenyl)piperazine (R is CONHCH (L) 1-{2- 2- (N,N-dimethylcarbamyl-5-methylmercapto-3-indolyl]ethyl}-4-rnethylpiperazine [R is (M) 1 [2(2-carbamyl-6-chloro-7-methyl-3-indolyl)ethyl]-4-(2-hydroxyethyl)piperazine (R is CONH (N) l {2 [2(N-methylcarbamyl)-5,6-dimethoxy-3-indolyl]ethyl}-4-(2-pyridyl)piperazine (R is CON CHC (O)l-{2-[2-N,N-dimethylcarbamyl)-5,6-dimethoXy-3-indolyl]ethyl}-4-2-(2-pyrimidyl)piperazine [R is (P)1-[2-(2-carbamyl-5,6-dimethoxy-3-indolyl)ethyl]-4-(Z-phenylethyl)piperazine (R is CONH (Q) l {2 [2(N-methylcarbamyl)-5,6-dimethoXy-3- indolyl]ethy1}-4-cinnamylpiperazine(R is CONHCH (R) l {2-[2-(N,N-dimethylcarbamyl)-5,6-dimethoxy 3indolyl]ethyl} 4 (4-hydroxyphenyl)piperazine [R is 3 2] i (S) 1-{2- 2-(N,N-dimethylcarbamyl) -5-methylsulfonyl-3-indolyl]ethyl}-4-(4-pyridyl)piperazine [R is (T) l [2 (2carbamyl-5-trifluoromethyl-3-indolyl)- ethyl] 4 (4 methylsulfinylphenyl)piperazine (R is CONH (U) 1-{2- [2- (N,N-dimethylcarbamyl-5-methylsulfinyl- 3 indolyl]ethyl} 4-(4-methylsulfonylphenyl)piperazine[R2 is (V) 1[2-(2-carbamyl-3-indolyl)ethyl]-4-(3,4-methylenedioxyphenyl)piperazine[R is CONH and (W) 1 {2-[2- (N-methylcarbamyl)-3-indolyl]ethyl}-4-(3,4-ethylenedioxyphenyl)piperazine (R is CONHCH EXAMPLE 15 l-[2-(2-sulfo-5,6-methylenedioxy-3-indolyl)ethyl] -4-(2- methoxyphenyl)piperazine A solution of 13 g. (0.034 mole) of l-[2-(5,6-methylenedioxy3 indolyl)ethyl]-4-(2-methoxyphenyl)piperazine and 65 g. (0.63 mole) ofsodium bisulfite in 1.5 liters of ethanol and 2 liters of water wasadjusted to pH 7, and air was bubbled through the mixture for seventytwohours. The solid which had separated was collected, dissolved in dilutesodium hydroxide and the solution extracted with ether. The aqueousrafiinate was acidified to pH 4.5, and the solid which separated wascollected and recrystallized from dilute acetic acid to give 5.8 g. of 1[2-(2-sulfo-5,6-methylenedioxy-3-indolyl)ethyl]-4-(2-methoxyphenyl)piperazine, M.P. 245.0-246.0 C. (corn).

14 I claim: 1. A compound having the formula where R is lower-alkyl,hydroXy-lower-alkyl, phenyl, phenyl-unbranched-lower-alkyl, cinnamyl,pyridyl, or 2- pyrimidyl; R is carbo-lower-alkoxy, carboxy, sulfo,hydroxymethyl, lower-alkanoyloxymethyl, carbamyl, N- loweralkylcarbamyl, N,N di lower alkylcarbamyl, formyl, orisonitrosomethylene, and alkali metal salts of compounds where R iscarboxy or sulfo; R is hydrogen, halogen, straight or unhinderedlower-alkyl, lower-alkoxy, lower-'alkylmercapto, trifiuoromethyl, orhydroxy; R is hydrogen, halogen, straight or unhindered lower-alkyl orlower-alkoxy, or R and R together represent methylenedioxy orethylenedioxy attached to adjacent carbon atoms, and wherein the benzenering of R as phenyl, phenylunbranched-lower-alkyl, or cinnamyl isunsubstituted or substituted by adjacent methylenedioxy or ethylenedioxyor by one or two of the same or different members of the groupconsisting of halogen, straight or unhindered loweralkyl, lower-alkoxy,loWer-alkylmercapto, trifiuoromethyl, or hydroxy.

' 2. A compound according to claim 1 Where R is unsubstituted-phenyl; Ris carbo-lower-alkoxy; and R and R are each lower-alkoxy.

3. A compound according to claim 1 where R isloweralkoXy-substituted-phenyl; R is carbo-lower-alkoxy; and R and R areeach lower-alkoxy.

4. A compound according to claim 1 where R ishydroxy-substituted-phenyl; R is carbo-lower-alkoxy; and R and R areeach lower-alkoxy.

5. A compound according to claim 1 where R is unsubstituted-phenyl; R iscarboxy or an alkali metal salt thereof; and R and R are eachlower-alkoxy.

6. A compound according to claim 1 where R is unsubstituted-phenyl; R ishydroxy-methyl; and R and R are each lower-alkoxy.

7. A compound according to claim 1 where R isloweralkoxy-substituted-phenyl; R is hydroxymethyl; and R and R are eachlower-alkoxy.

8. A compound according to claim 1 where R isloweralkoxy-substituted-phenyl; R is sulfo; and R and R togetherrepresent methylenedioxy attached to adjacent carbon atoms.

9. 1 [2 -(2-carbethoxy-S,6-dimeth0Xy-3-indolyl)-ethyl]-4-phenylpiperazine accordingto claim 2 where R is carbethoxy; and R and R together are5,6-dimethoxy.

10. 1 [2 (2-carbomethoxy-5,6 dimethoxy-3-indolyl)-ethyl]-4-phenylpiperazine according to claim 2 where R is carbomethoxy;and R and R together are 5,6-dimethoxy.

11. 1 [2- (2-carbopropoxy-5,6-dimethoxy-3-indolyl)ethyl]-4-phenylpiperazine according to claim 2 where R is carbopropoxy;and R and R together are 5,6-dimethoxy.

12. 1[2-(Z-carbethoxy-S,G-dimethoxy-S-indolyl)-ethyl]-4-(2-methoxyphenyl)piperazineaccording to claim 3 where R is Z-methoxyphenyl; R is carbethoxy; and Rand R together are 5,6-dimethoxy.

13. 1[2-(2-carbethoxy-5,6-dimethoxy-3-indolyl)-ethyl]-4-(4-hydroxyphenyl)piperazineaccording to claim 4 wherein R is 4-hydroxyphenyl; R is carbethoxy; andR and R together are 5,6-dimethoxy.

14. 1 [2- (2-carboxy-5,6-dimethoxy-3-indolyl)ethyl]- 154-phenyipiperazine according to claim 5 where R is carboxy; and R and Rtogether are 5,6-dimethoxy,

15. 1 [2(Z-hydroxymethyl-5,-6-dimethoxy-3-indo1y1)-ethyl]-4-phenylpiperazine according to claim 6 where R and R togetherare 5,6-dimethoxy.

16. 1 [2-(2-hydroxymethyl-S,6-dimethoxy-3-ind01y1)-ethyl]-4-(Z-methoxyphenyl)piperazine according to claim 7 where R isZ-methoxyphenyl; and R and 'R together are 5,6-dimethoxy.

17. 1 [2(2-sulfo-5,6-methy1enedioxy-3-ind0lyl)-ethyl]-4-(Z-methoxyphenyl)piperazineaccording to claim 8 where R is Z-methoxyphenyl; and R and R togetherare 5,6-methy1enedioxy.

References Cited DONALD G. DAUS, Primary Examiner US. Cl. X.R.

mum No. 3,563,378 Dated February 9, 971

Inventor(s) S mA hep It is certified that error appears in theabove-identified paten and that said Letters Patent are hereby correctedas shown below:

r Column 1, line 25, "which is" should read --which in--.

Column 2, line 32, "(2-hydroxyethyl indole" should read--(2-hydroxyethyl)indole--.

Column 5, line 28, "abovedescribed" should read --above cribed--'-.

Column 9, line 54, "methylcercaptofi should read --methy mercapto--.

Column 10, line #0, "ethyl)" should read --ethyl]--.

Column 12, line 55, 1- [2-isonitrosomethylene;. $1101 read --l-[2-(2-nitroisomethylene-. line 67, R is should read (R is Column 13,line 12, "R is. should read [R 1 line 28 "CONCHC should ead --CONHCHline 36, [2- N,N-. n) should Fead [2-(N N-. 1 ne 51, 4-2-(2- r1 shouldread l-(2-pyrimidyl5--.

Column 14, line 75, "wherein" should read "where".

Signed and sealed this 11th day of January 1972.

(SEAL) Attest:

EDWARD M.FLETCHER, JR. ROBERT GOT'ISCHALK Attesting Officer ActingCommissioner of Paton

